W. E. Dodson

Subtemporal transparahippocampal amygdalohippocampectomy for surgical treatment of mesial temporal lobe epilepsy. Technical note.

Amygdalohippocampectomy (AH) is an accepted surgical option for treatment of medically refractory mesial temporal lobe epilepsy. Operative approaches to the amygdala and hippocampus that previously have been reported include: the sylvian fissure, the superior temporal sulcus, the middle temporal gyrus, and the fusiform gyrus. Regardless of the approach, AH permits not only extirpation of an epileptogenic focus in the amygdala and anterior hippocampus, but interruption of pathways of seizure spread via the entorhinal cortex and the parahippocampal gyrus. The authors report a modification of a surgical technique for AH via the parahippocampal gyrus, in which excision is limited to the anterior hippocampus, amygdala and parahippocampal gyrus while preserving the fusiform gyrus and the rest of the temporal lobe. Because transparahippocampal AH avoids injury to the fusiform gyrus and the lateral temporal lobe, it can be performed without intracarotid sodium amobarbital testing of language dominance and language mapping. Thus the operation would be particularly suitable for pediatric patients in whom intraoperative language mapping before resection is difficult.

Phenytoin elimination in newborns

We measured the apparent half-life (t50%) of phenytoin (PHT) 30 times in 16 infants (aged 2 to 36 days) who had seizurtes. During the first week of life, the t50% s ranged from 6 to 140 hours. After the first week, the concentration dependence of PHT elimination was demonstrated; the t50% was related to the initial concentration (CJ. The t50% also decreased with postnatal age. Controlling for a C1 of 18 mg per liter, the average t50% decreased threefold between the first (57.3 ± 48.2 hours) and fourth weeks (19.7 ± 1.31). In newborns, both age-related changes and the concentration dependence of PHT elimination can cause PHT levels to decrease when constant doses are given.

Phenytoin and carbamazepine, alone and in combination Anticonvulsant and neurotoxic effects

Comedication with phenytoin and carbamazepine is frequently used in patients with refractory seizures, although the benefit of this strategy has not been established. To assess whether the combination is a rational anticonvulsant treatment, we determined the therapeutic index (toxicity:efficacy ratio) for the drugs, alone and together, in mice. The individual agents were virtually identical in anticonvulsant and neurotoxic activity, and combined use had no additional therapeutic advantage. Analysis of drug concentrations in brain showed an additive pharmacodynamic interaction for phenytoin and carbamazepine, indicating that the combination is unlikely to be superior to either drug alone. Thus, we find no experimental justification for the simultaneous use of phenytoin and carbamazepine in the treatment of epilepsy.

Primdone, phenobarbital, and PEMA I. Seizure protection, neurotoxicity, and therapeutic index of individual compounds in mice

Neurotoxicity and protection against maximal electroshock and Metrazol seizures from primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA) were determined in mice for each drug separately and expressed in terms of brain concentrations. Compared with PB, PEMA was 16 times less potent against electroshock and Metrazol seizures but only 8 times less toxic. Primidone was markedly less neurotoxic than PB and equally potent against electroshock, but PRM had no effect against Metrazol or bicuculline. PRM is a relatively nontoxic anticonvulsant with a different action than PB, and PEMA is both a weak and a relatively toxic anticonvulsant.Neurotoxicity and protection against maximal electroshock and Metrazol seizures from primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA) were determined in mice for each drug separately and expressed in terms of brain concentrations. Compared with PB, PEMA was 16 times less potent against electroshock and Metrazol seizures but only 8 times less toxic. Primidone was markedly less neurotoxic than PB and equally potent against electroshock, but PRM had no effect against Metrazol or bicuculline. PRM is a relatively nontoxic anticonvulsant with a different action than PB, and PEMA is both a weak and a relatively toxic anticonvulsant.

Interactions between prim done, carbamazepine, and nicotinamide

The effect of nicotinamide on the conversion of primidone to phenobarbital was0 studied in mice and in three epileptic patients. In mice, 200 mg per kilogram of nicotinamide increased the half-life of primidone by 47.6%, and the conversion to phenobarbital and phenylethylmalonamide was decreased by 32.4% and 14.5%, respectively. Nicotinamide also decreased the conversion of primidone to phenobarbital in patients. The dose of nicotinamide correlated directly with the primidone:phenobarbital ratio (r = 0.861, p < 0.01). Nicotinamide also increased carbamazepine levels in two patients treated with this drug. The data demonstrate that nicotinamide inhibits metabolism of primidone in mice and metabolism of primidone and carbamazepine in humans. This probably occurs by inhibition of cytochrome P-450 by nicotinamide.

Primidone, phenobarbitai and PEMA II. Seizure protection, neurotoxicity, and therapeutic index of varying combinations in mice

Neurotoxicity and protection against maximal electroshock (MES) and pentylenetrazol (Metrazol) seizures were determined in mice for various combinations of primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA). The results suggest that PRM and PB together are superior to either one alone in terms of spectrum of activity and relative toxicity. The protection against Metrazol and the toxicity of PB are both potentiated by PEMA at low concentrations. PEMA also potentiates the toxicity of combined PRM plus PB, without altering their protection against MES, thus lowering their therapeutic index. We conclude that PRM and PB together have an advantage over PB alone, especially when their brain concentration ratio is at or above 1 and PEMA concentrations are low. These conditions are usually not present at steady state in patients treated with PRM.Neurotoxicity and protection against maximal electroshock (MES) and pentylenetrazol (Metrazol) seizures were determined in mice for various combinations of primidone (PRM), phenobarbital (PB), and phenyl-ethylmalonamide (PEMA). The results suggest that PRM and PB together are superior to either one alone in terms of spectrum of activity and relative toxicity. The protection against Metrazol and the toxicity of PB are both potentiated by PEMA at low concentrations. PEMA also potentiates the toxicity of combined PRM plus PB, without altering their protection against MES, thus lowering their therapeutic index. We conclude that PRM and PB together have an advantage over PB alone, especially when their brain concentration ratio is at or above 1 and PEMA concentrations are low. These conditions are usually not present at steady state in patients treated with PRM.